The pyrrolidine fragment is a privileged scaffold within chiral ligands employed in coordination complexes exhibiting catalytic activity in asymmetric reactions and, more recently, as enantioselective organocatalysts per se. Likewise, the employment of (S)-proline as starting material constitutes the most direct form to synthesize those chiral derivatives. Afterwards, a preliminary evaluation of the catalytic performance of proline-derived compounds consists of screening many prochiral substrates in well standardized model reactions such as Michael additions and Mannich reactions, with the aim of identifying “broad spectrum” catalysts for more complex synthetic applications. Therefore, a central part of this process involves the fast and direct measurement of enantioselectivities of optically active adducts. The growing development of chiral stationary phases and thus, the wide commercial availability of chiral columns have consolidated high performance liquid chromatography (HPLC) as the preferred technique to identify the most effective catalysts.

Organocatalysis constitutes one of the most relevant advances in the science of chemistry in the XXI Century. In particular, organocatalytic reactions are now a powerful strategy for the stereoselective synthesis of chiral molecules. In this article, the fundaments and enormous potential of organocatalysis are presented, together with some particular examples of developments taking place in our laboratories. It is evident the necessity to consolidate the area of organocatalysis in Mexico in order to benefit from the academic (i.e., developing new conceptual models and novel organocatalytic systems) and practical uses (for example, application of efficient and environmentally friendly production of chemicals at an industrial scale).

La organocatálisis constituye uno de los avances más importantes en el área de la química del siglo XXI. En particular, las reacciones organocatalíticas se han constituido como una herramienta poderosa para la construcción estereoselectiva de estructuras moleculares quirales. En este artículo se presentan los fundamentos y el enorme potencial de la organocatálisis, junto con algunos ejemplos particulares de desarrollos que se han dado en nuestros laboratorios. Es evidente que es necesario consolidar el campo de la organocatálisis en México, y en efecto varios grupos de investigación están iniciando trabajos originales en esta área.

The use of microwave heating is a valuable tool for synthetic chemists. Being able to reduce reaction times and to increase product yield, this methodology offers to organic chemists the potential to optimize reaction processes. Additionally, microwave-assisted reactions provide more environmentally friendly reaction conditions. In this report, we describe results in the optimization of several organic reactions employed in the synthesis of various chiral molecules such as heterocycles, β-amino acids, and β-peptides, among others.

El uso de calentamiento por microondas es una valiosa herramienta para los químicos sintéticos. Esta metodología permite reducir los tiempos de reacción e incrementar el rendimiento de los productos, lo que equivale a optimizar los procesos de interés. Aunado a esto, las reacciones asistidas por microondas son más amigables al medio ambiente. En este trabajo se describen algunos resultados obtenidos en la optimización de varias reacciones orgánicas utilizadas para la síntesis de diversas moléculas quirales tales como heterociclos, β-aminoácidos y β-péptidos, entre otros.

The influence of the framework structure in C2-symmetric N,N'-di[α-phenylethyl]diamines as chiral derivatizing agents, on their effectiveness for the determination of the enantiomeric composition of chiral secondary alcohols by 31P-NMR spectroscopy of derived diastereomeric phosphonamides, is described.

Se describe la influencia de la estructura de N,N'-di[α-feniletil]-diaminas con eje de simetría C2, como agentes derivatizantes quirales en la determinación de la composición enantiomérica de alcoholes secundarios quirales empleando RMN de 31P.

Variable-temperature ¹H and 13C NMR spectroscopy of substituted cyclohexanes permitted the evaluation of the thermodynamic parameters for the axial ⇌ equatorial conformational equilibria when the substituent is methyl, ethyl, isopropyl, tert-butyl, benzyl, and the sulfur-containing methylthio, methylsulfinyl, and methylsulfonyl. Interpretation of the results confirms the premise that a proper understanding of conformational preferences requires the knowledge of the enthalpic and entropic contributions to the conformational free energy differences. A comment on the determination of thermodynamic parameters by means of theoretical methods is also included.

Estudios espectroscópicos mediante resonancia magnética nuclear a diferentes temperaturas hicieron posible la evaluación de los parámetros termodinámicos asociados a equilibrios conformacionales axial ⇌ ecuatorial en ciclohexanos sustituidos, en los que el sustituyente es metilo, etilo, isopropilo, terbutilo, bencilo, o algunos de los grupos tiometilo, metilsulfinilo o metilsulfonilo. La interpretación de los resultados obtenidos muestra que para alcanzar el entendimiento correcto de las preferencias conformacionales es necesario conocer las componentes entálpicas y entrópicas además de las diferencias en la energía libre conformacional. Finalmente, se presenta también el uso de métodos teóricos para la determinación de parámetros termodinámicos.

β-Alanine, an inexpensive β-amino acid, was converted into the 2-phenylperhydropyrimidin-4-one derivative (1), which can be alkylated with high diastereoselectivity via the corresponding enolate. The high stereoselectivity observed for the reaction of (1)-Li with electrophiles seems to be due to steric hindrance generated by an axial disposition of the phenyl group at C(2), which directs addition from the enolate face opposite to this group. These results pave the road to the enantioselective synthesis of α-substituted β-amino acids.

β-Alanina, un aminoácido accesible, fue transformado al derivado 2-fenilperhidropirimidín-4-ona (1), que puede ser alquilado con alta diastereoselectividad mediante el enolato correspondiente. La alta estereoselectividad observada para la reacción de (1)-Li con electrófilos parece ser debida al impedimento generado por la disposición axial del grupo fenilo en C(2), el cual dirige la adición por la parte opuesta a este grupo. Estos resultados facilitan el camino a la síntesis enantioselectiva de β-aminoácidos substituidos en α.

beta-Alanina, matéria-prima aquiral e de baixo custo, foi convertida na amida quiral 1 em 53% de rendimento global. A alquilação de (R,R)-1 requereu a formação de seu diânion, (R,R)-1-Li2 que foi alcançada de maneira mais eficiente pela metação direta com dois equivalentes de n-BuLi em solução de THF a -78 ºC. O tratamento de (R,R)-1-Li2 com vários haletos de alquila forneceu os produtos monoalquilados 3-6 em 24-85% de rendimento e 65-86% de diastereosseletividade. O efeito do aditivo LiCl ou de HMPA como co-solvente na diastereosseletividade da reação de alquilação foi essencialmente desprezível, embora os reandimentos tenham geralmente aumentado. A correlação química do diastereoisômero majoritário da reação de metilação com (S)-alfa-metil-beta-alanina mostra que a adição do eletrófilo ocorre preferencialmente na face Si do enolato. Esta conclusão é também apoiada por estudos de modelagem molecular (ab initio HF/3-21G) que indicam que a conformação de menor energia para (R,R)-1-Li2 apresenta a face Re do enolato mais impedida estericamente. Os estudos teóricos também ofereceram indicações úteis sobre a importância da ligação de hidrogênio e de interações atrativas pi-pi em (R,R)-1. Adicionalmente, os cálculos prevêem um papel determinante para a quelação N-Li-O em (R,R)-1-Li assim como um interessante configuração de tripleto iônico para o diânion de lítio (R,R)-1-Li2.

Achiral, inexpensive beta-alanine was converted into the title chiral amide 1 in 53% overall yield. C-Alkylation of (R,R)-1 required formation of its dianion derivative, (R,R)-1-Li2, which was best achieved by direct metallation with two equivalents of n-BuLi in THF solution and at -78°C. Treatment of (R,R)-1-Li2 with various alkyl halides afforded the monoalkylated products 3-6 in 24-85% yield and 65-86% diastereoselectivity. The effect of LiCl additive or HMPA co-solvent on the diastereoselectivity of the alkylation reaction was essentially negligible, although reaction yields generally improved. Chemical correlation of the major diastereomer from the methylation reaction with (S)-alpha-methyl-beta-alanine shows that addition of the electrophile takes place preferentially on the enolate's Si face. This conclusion is also supported by molecular modelling studies (ab initio HF/3-21G), which indicate that the conformation of lowest energy for (R,R)-1-Li2 presents a more sterically hindered Re face of the enolate. The theoretical studies also provided useful insight into the importance of hydrogen bonding and attractive <FONT FACE=Symbol>p-p</FONT> interactions in (R,R)-1. Furthermore, the calculations predict a determining role for N-Li-O chelation in (R,R)-1-Li, as well as an interesting ion triplet configuration for dilithium dianion (R,R)-1-Li2.